Lithium Prophylaxis for Chronic Cluster Headache Lee Kudrow, M.D. California Medical Clinic for Headache, Inc. (Dr. Kudrow). Reprint requests to: California Medical Clinic for Headache, Inc., 16542 Ventura Boulevard, Encino, California, (Dr. Kudrow). Accepted for publication: 11/15/76. SYNOPSIS Thirty-two patients with chronic cluster headache, not responding to conventional therapy, were treated with lithium carbonate for 32 weeks. Treatment was discontinued in 4 cases because of intolerable side effects. Marked and continued improvement occurred in 27 of 28 patients throughout the treatment period. Twenty-five percent of all patients had mild or transient side effects without increased serum lithium levels. Long-term prophylactic lithium maintenance treatment is efficacious in selected cases of chronic cluster headache. (Headache 17: 15-18, 1977) THE CHRONIC FORM of cluster headache was clearly established and distinguished from the episodic type by Ekbom in 1971.1 The features of chronic cluster headache are: absence of remission periods; increased headache attack frequency; and diminished responsiveness to prophylactic drugs such as ergotamines, methysergide or steroids. This often leads to social and occupational incapacitation of the patient. Promising results of lithium treatment in 3 patients with chronic cluster headache2 have been reported and 2 patients have been maintained on lithium for approximately 18 months with fairly good results.* It had been suggested that lithium may be of value in chronic cluster3 presumably because this disorder shares several characteristics with manic-depressive disease which is responsive to lithium therapy.4 I report herein on the efficacy of initial and long-term prophylactic lithium therapy in chronic cluster headache. Because patients with cluster headache are not significantly influenced by placebo effects, subtle interpersonal or environmental stimuli, this study is neither blind nor patient-controlled. PATIENTS AND METHODS Chronic cluster headache patients resistant to or intolerant of methysergide, prednisone and ergotamine medications were studied, but when lithium was contraindicated, patients were excluded. The diagnosis of cluster headache was based on criteria of the Ad Hoc Committee on the Classification of Headache,5 modified for the chronic type by Ekbom.1 Patients were advised to maintain their usual salt intake; refrain from use of all other drugs; and report untoward effects. They were instructed to record the headaches daily by rated severity (1=mild, 2=moderate, 3=severe). A headache index (HAI) was derived from the weekly frequency times rated severity. Lithium carbonate 300-600 mg. a day was used the first week, increasing to 600-900 mg. by the fourth week. The maintenance dose depended on clinical response and severity of side effects rather than serum lithium levels. The dose of lithium was reduced if serum levels were above 1.2 meq./L. Serum lithium levels were measured weekly for a month and monthly thereafter. The Headache Index Ratio (HAR) was calculated. This defines quantitative improvement by dividing "lithium treatment
TABLE 1 CHARACTERISTICS OF PRIMARY AND SECONDARY CHRONIC CLUSTER PATIENTS MEAN PRE-TREATMENT CHRONIC MEAN MEAN STATE HEADACHE CLUSTER HEADACHE TYPES N AGE SEX (YRS.) INDEX* Primary Chronic 19 36 3 Women 4.4 Secondary Chronic 13 42 2 Women 2.3 Total or Average 32 39 5 Women 3.5 * Pre-Treatment mean headache index = Weekly headache frequency x rated severity.
51.2 53.8 52.3
HAl" by the "pre-treatment HAl". The percent improvement is the reciprocal number of the HAR x 100. Of 32 patients in this study (Table 1), 19 had primary chronic cluster headache (never having had episodic cluster patterns); 13 patients had secondary chronic cluster headache (history of remissions, though none in recent years). The male-to-female ratio was 5.4:1. There was little clinical difference between primary and secondary chronic cluster patients, but duration of the chronic cluster state was longer for the primary than for the secondary group (Table 1). RESULTS The side effects of lithium therapy are given in Table 2. Three patients dropped from the study had headache. This headache was similar in all; moderately severe throbbing occipital pain lasting 6-12 hours. When lithium was stopped, there was complete relief. Cluster headaches were easily distinguished by the patients from "lithium headache". One patient had anorexia, vague abdominal discomfort, persistent nausea and vomiting, and rapid weight loss. Discontinuation of lithium resulted in relief of symptoms. His highest serum lithium level was 1.2 meq./L. Eight patients completing the study had 2 or more side effects of lithium during the early weeks. Five patients had mild tremor, which increased on exertion. Often this side effect continued throughout the study. Four patients had mild mental dysfunction such as confusion, decreased concentration, and memory defect. Decreasing the lithium dose eliminated mental dysfunction (Table 2). These patients used higher doses of lithium, 1200-1500 mg./day. However, serum lithium levels remained below 1.0 meq./L. One out of 28 patients completing the study had no benefit from lithium therapy (Table 3). ImproveTABLE 2 FREQUENCY AND DESCRIPTION OF SIDE EFFECTS DURING LITHIUM THERAPY IN 32 PATIENTS WITH CHRONIC CLUSTER HEADACHES SEVERITY OF SIDE EEFECTS N (%) DESCRIPTION N Severe-Requiring Discontinuation 4 (12.5%) "Lithium Headache" 3 Abdominal Pain and Vomiting 1 Mild-Allowing Continuation 8 (25%) Tremor 5 Thought Dysfunction 4 Lethargy 3 Diarrhea 3 Insomnia 2 Lightheadedness 2
TABLE 3 RESULTS OF LITHIUM TREATMENT OF 26 PATIENTS WITH CHRONIC CLUSTER HEADACHES IMPROVEMENT* 90 MEAN CLUSTER TYPES N AGE N (%) N (%) N (%) Primary 17 35 1 (6) 6 (38) 9 (56) Secondary 11 41 0 5 (50) 5 (50) Total or Average 28 38 1 (4) 11 (42) 14 (54) * Derived from headache index ratios.
ment for primary and secondary cluster headache patients was not significantly different. The mean percentage in weekly improvement, lithium blood levels and dose are shown in Figure 1. Throughout the first 8 weeks with an increase in daily dose of lithium carbonate, the success rate also increased. After the 12th week improvement continued in spite of a lower, stable serum lithium level. In general the serum lithium findings remained proportional to the oral dose level. An attempt was made to distinguish between therapeutic failures and responders by age, sex, pre-treatment headache index or duration of illness (Table 4). The differences between the two groups were not significant. DISCUSSION The results of this study show that lithium carbonate prophylaxis was beneficial in chronic cluster headache. Moderately long-term therapy did not lead to lithium tolerance and even lower lithium maintenance doses provided continued improvement after the twelfth week. During the first few weeks, the lithium dose was kept low, but no relationship between later lithium levels and side effects were observed, except perhaps with mental dysfunction. Transient side effects in lithium-treated affective disorders are reported to have little relationship to serum lithium values also.6
TABLE 4 COMPARISON OF MEAN AGE, SEX, HEADACHE INDEX AND DURATION OF ILLNESS BETWEEN THERAPEUTIC FAILURES AND SUCCESSES MEAN SEX RATIO HEADACHE MEAN CHRONIC GROUPS N AGE (M:F) INDEX STATE (YRS.) Failures 5* 37 6:1 54 4.75 Improved 27 39 6.3:1 * 4 of 5 patients discontinued Lithium because of intolerable side effects.
52
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Minimal side effects such as tremor, mild confusion, memory changes, decreased concentration ability, abdominal discomfort, diarrhea, nausea, lethargy, insomnia and lightheadedness, occurred in 28.6% of our completed study population. A similar incidence in manic-depressives was reported by Schou.7 Muscle weakness, thirst, and polyuria are common side effects during lithium therapy, yet these were notably absent in our patients. In 3 patients who were unable to take lithium because of side effects, moderately severe, deep occipital, throbbing headaches of 6-12 hours' duration occurred. This was quite unlike the cluster attacks. The uniformity of the description of headache, and remission after lithium was withdrawn suggests a cause-and-effect relationship. A review of the literature showed no mention of "lithium headache" as a side effect. This suggests that lithium produced headache may occur in cluster headache patients only. Although the mechanism of this headache is not clear, the description is similar to headaches associated with systemic disorders having an intracranial pain mechanism.8 "Lithium headache" may therefore arise intracranially also. Patients who had improved on lithium often showed dramatic relief during the first week and continued to remain almost symptom-free for the duration of this study. Not infrequently, however, they would have a "run" of daily mild cluster attacks for 3 or 4 consecutive days every 3-6 weeks. Fewer still developed occasional moderate to severe cluster attacks without change in medication or other provocation. Because of the high incidence of alcohol use among cluster patients,9 it was common for them to drink in spite of warnings. These patients noted that an otherwise successful lithium regimen did not prevent an alcohol-induced cluster headache. This suggests that lithium suppresses mechanisms responsible for the spontaneous cluster attack without interfering with alcohol-induced attacks. Lithium may act centrally to decrease excessive autonomic activity associated with the cluster state. Lower-threshold, spontaneous attacks are inhibited, but this is not sufficient to prevent the vasomotor response to alcohol. High success rates were achieved with serum lithium levels ranging from .4 to 1.0 meq./L. This variation in therapeutic response may reflect on intracellular lithium concentration rather than serum levels. Clinical responses to lithium therapy may depend on genetically determined cellular membrane differences, and are better correlated to an intracellular/extracellular lithium ratio rather than to serum levels alone.10,11 The response of manic-depressive disorder to lithium prophylaxis and the efficacy of lithium in chronic cluster headache suggest that other similarities between the two disorders should be explored. REFERENCES 1.
Ekbom, K., Olivarius, B. de Fine: Chronic migrainous neuralgia-diagnostic and therapeutic aspects. Headache 11:97-101, 1971.
2.
Ekbom, K.: Litium vid kroniska symptom av cluster headache. Preliminärt Meddelande. Opusc. Med. 19:148-156, May 1974.
3.
Graham, J.R.: Treatment of cluster headache (Workshop). Chairman: Ottar Sjaastad. Sixteenth Annual Meeting, American Association for the Study of Headache, June 1974.
4.
Gershon, S., Shopsin, B. (Editors): Lithium. Its Role in Psychiatric Research and Treatment. New York-London: Plenum Press, 1973.
5.
Ad Hoc Committee on the Classification of Headache. J.A.M.A. 179:717-718, 1962.
6.
Schou, M.: Lithium in psychiatric therapy and prophylaxis. J. Psychiat. Res. 6:67-95. Great Britain: Pergamon Press, 1968.
7.
Schou, M., Baastrup, P.C., Grof, P., Weis, P., Angst, J.: Pharmacological and clinical problems of lithium prophylaxis. Brit. J. Psychiat. 16:615, 1971.
8.
Kudrow, L.: Systemic causes of headache. Postgrad. Med. 56:105-111, 1974.
9.
Kudrow, L.: Physical and personality characteristics in cluster headache. Headache 13:197-202, 1974.
10.
Dorus, E., Pandey, G.N., Frazer, A., Mendels, J.: Genetic determinant of lithium ion distribution. 1. An in vitro mono-zygotic-dizygotic twin study. Arch. Gen. Psychiat. 31:463-465, 1974.
11.
Schless, A.P., Frazer, A., Mendels, J., Pandey, G.N., Theodorides, V.J.: 2. An in vivo study of lithium ion distribution across erythrocytes membranes. Arch. Gen. Psychiat. 32:337-340, 1975.
TABLE 1 CHARACTERISTICS OF PRIMARY AND SECONDARY CHRONIC CLUSTER PATIENTS MEAN PRE-TREATMENT CHRONIC MEAN MEAN STATE HEADACHE CLUSTER HEADACHE TYPES N AGE SEX (YRS.) INDEX* Primary Chronic 19 36 3 Women 4.4 Secondary Chronic 13 42 2 Women 2.3 Total or Average 32 39 5 Women 3.5 * Pre-Treatment mean headache index = Weekly headache frequency x rated severity.
51.2 53.8 52.3
HAl" by the "pre-treatment HAl". The percent improvement is the reciprocal number of the HAR x 100. Of 32 patients in this study (Table 1), 19 had primary chronic cluster headache (never having had episodic cluster patterns); 13 patients had secondary chronic cluster headache (history of remissions, though none in recent years). The male-to-female ratio was 5.4:1. There was little clinical difference between primary and secondary chronic cluster patients, but duration of the chronic cluster state was longer for the primary than for the secondary group (Table 1). RESULTS The side effects of lithium therapy are given in Table 2. Three patients dropped from the study had headache. This headache was similar in all; moderately severe throbbing occipital pain lasting 6-12 hours. When lithium was stopped, there was complete relief. Cluster headaches were easily distinguished by the patients from "lithium headache". One patient had anorexia, vague abdominal discomfort, persistent nausea and vomiting, and rapid weight loss. Discontinuation of lithium resulted in relief of symptoms. His highest serum lithium level was 1.2 meq./L. Eight patients completing the study had 2 or more side effects of lithium during the early weeks. Five patients had mild tremor, which increased on exertion. Often this side effect continued throughout the study. Four patients had mild mental dysfunction such as confusion, decreased concentration, and memory defect. Decreasing the lithium dose eliminated mental dysfunction (Table 2). These patients used higher doses of lithium, 1200-1500 mg./day. However, serum lithium levels remained below 1.0 meq./L. One out of 28 patients completing the study had no benefit from lithium therapy (Table 3). ImproveTABLE 2 FREQUENCY AND DESCRIPTION OF SIDE EFFECTS DURING LITHIUM THERAPY IN 32 PATIENTS WITH CHRONIC CLUSTER HEADACHES SEVERITY OF SIDE EEFECTS N (%) DESCRIPTION N Severe-Requiring Discontinuation 4 (12.5%) "Lithium Headache" 3 Abdominal Pain and Vomiting 1 Mild-Allowing Continuation 8 (25%) Tremor 5 Thought Dysfunction 4 Lethargy 3 Diarrhea 3 Insomnia 2 Lightheadedness 2
TABLE 3 RESULTS OF LITHIUM TREATMENT OF 26 PATIENTS WITH CHRONIC CLUSTER HEADACHES IMPROVEMENT* 90 MEAN CLUSTER TYPES N AGE N (%) N (%) N (%) Primary 17 35 1 (6) 6 (38) 9 (56) Secondary 11 41 0 5 (50) 5 (50) Total or Average 28 38 1 (4) 11 (42) 14 (54) * Derived from headache index ratios.
ment for primary and secondary cluster headache patients was not significantly different. The mean percentage in weekly improvement, lithium blood levels and dose are shown in Figure 1. Throughout the first 8 weeks with an increase in daily dose of lithium carbonate, the success rate also increased. After the 12th week improvement continued in spite of a lower, stable serum lithium level. In general the serum lithium findings remained proportional to the oral dose level. An attempt was made to distinguish between therapeutic failures and responders by age, sex, pre-treatment headache index or duration of illness (Table 4). The differences between the two groups were not significant. DISCUSSION The results of this study show that lithium carbonate prophylaxis was beneficial in chronic cluster headache. Moderately long-term therapy did not lead to lithium tolerance and even lower lithium maintenance doses provided continued improvement after the twelfth week. During the first few weeks, the lithium dose was kept low, but no relationship between later lithium levels and side effects were observed, except perhaps with mental dysfunction. Transient side effects in lithium-treated affective disorders are reported to have little relationship to serum lithium values also.6
TABLE 4 COMPARISON OF MEAN AGE, SEX, HEADACHE INDEX AND DURATION OF ILLNESS BETWEEN THERAPEUTIC FAILURES AND SUCCESSES MEAN SEX RATIO HEADACHE MEAN CHRONIC GROUPS N AGE (M:F) INDEX STATE (YRS.) Failures 5* 37 6:1 54 4.75 Improved 27 39 6.3:1 * 4 of 5 patients discontinued Lithium because of intolerable side effects.
52
3.21
Minimal side effects such as tremor, mild confusion, memory changes, decreased concentration ability, abdominal discomfort, diarrhea, nausea, lethargy, insomnia and lightheadedness, occurred in 28.6% of our completed study population. A similar incidence in manic-depressives was reported by Schou.7 Muscle weakness, thirst, and polyuria are common side effects during lithium therapy, yet these were notably absent in our patients. In 3 patients who were unable to take lithium because of side effects, moderately severe, deep occipital, throbbing headaches of 6-12 hours' duration occurred. This was quite unlike the cluster attacks. The uniformity of the description of headache, and remission after lithium was withdrawn suggests a cause-and-effect relationship. A review of the literature showed no mention of "lithium headache" as a side effect. This suggests that lithium produced headache may occur in cluster headache patients only. Although the mechanism of this headache is not clear, the description is similar to headaches associated with systemic disorders having an intracranial pain mechanism.8 "Lithium headache" may therefore arise intracranially also. Patients who had improved on lithium often showed dramatic relief during the first week and continued to remain almost symptom-free for the duration of this study. Not infrequently, however, they would have a "run" of daily mild cluster attacks for 3 or 4 consecutive days every 3-6 weeks. Fewer still developed occasional moderate to severe cluster attacks without change in medication or other provocation. Because of the high incidence of alcohol use among cluster patients,9 it was common for them to drink in spite of warnings. These patients noted that an otherwise successful lithium regimen did not prevent an alcohol-induced cluster headache. This suggests that lithium suppresses mechanisms responsible for the spontaneous cluster attack without interfering with alcohol-induced attacks. Lithium may act centrally to decrease excessive autonomic activity associated with the cluster state. Lower-threshold, spontaneous attacks are inhibited, but this is not sufficient to prevent the vasomotor response to alcohol. High success rates were achieved with serum lithium levels ranging from .4 to 1.0 meq./L. This variation in therapeutic response may reflect on intracellular lithium concentration rather than serum levels. Clinical responses to lithium therapy may depend on genetically determined cellular membrane differences, and are better correlated to an intracellular/extracellular lithium ratio rather than to serum levels alone.10,11 The response of manic-depressive disorder to lithium prophylaxis and the efficacy of lithium in chronic cluster headache suggest that other similarities between the two disorders should be explored. REFERENCES 1.
Ekbom, K., Olivarius, B. de Fine: Chronic migrainous neuralgia-diagnostic and therapeutic aspects. Headache 11:97-101, 1971.
2.
Ekbom, K.: Litium vid kroniska symptom av cluster headache. Preliminärt Meddelande. Opusc. Med. 19:148-156, May 1974.
3.
Graham, J.R.: Treatment of cluster headache (Workshop). Chairman: Ottar Sjaastad. Sixteenth Annual Meeting, American Association for the Study of Headache, June 1974.
4.
Gershon, S., Shopsin, B. (Editors): Lithium. Its Role in Psychiatric Research and Treatment. New York-London: Plenum Press, 1973.
5.
Ad Hoc Committee on the Classification of Headache. J.A.M.A. 179:717-718, 1962.
6.
Schou, M.: Lithium in psychiatric therapy and prophylaxis. J. Psychiat. Res. 6:67-95. Great Britain: Pergamon Press, 1968.
7.
Schou, M., Baastrup, P.C., Grof, P., Weis, P., Angst, J.: Pharmacological and clinical problems of lithium prophylaxis. Brit. J. Psychiat. 16:615, 1971.
8.
Kudrow, L.: Systemic causes of headache. Postgrad. Med. 56:105-111, 1974.
9.
Kudrow, L.: Physical and personality characteristics in cluster headache. Headache 13:197-202, 1974.
10.
Dorus, E., Pandey, G.N., Frazer, A., Mendels, J.: Genetic determinant of lithium ion distribution. 1. An in vitro mono-zygotic-dizygotic twin study. Arch. Gen. Psychiat. 31:463-465, 1974.
11.
Schless, A.P., Frazer, A., Mendels, J., Pandey, G.N., Theodorides, V.J.: 2. An in vivo study of lithium ion distribution across erythrocytes membranes. Arch. Gen. Psychiat. 32:337-340, 1975.
